Tumor resident memory CD8 T cell formation and concomitant tumor immunity is CD40L dependent and CD4 independent.

The implantation of cancer cell lines into immunocompetent mice acts as a vaccination event, resulting in T cell immunity that impacts both tumor progression and the response to subsequent therapy. We have previously shown that blocking immunity at tumor implantation using anti-CD40L antibodies blocks development of an intratumoral antigen-specific CD8 T cell population with tissue resident memory (Trm) phenotypes, and also limits responsiveness to radiation therapy and immunotherapy combinations. Using pancreatic tumors derived from Pdx1-Cre and Pdx1-Cre /R26LSL-LSIY mice crossed with KrasLSL-G12D/+Tp53LSL-R172H/+ mice, we explored the role of CD4 T cells in providing CD40-CD40L help to generate Trm and conventional T central memory CD8 T cells (Tcm) cells in the tumor and systemically. Using depleting antibodies, we identified that Trm cells in the tumor could form independently of CD4 T cells but were lost following CD40L blockade. By contrast, systemically circulating Tcm cells that could re-expand after antigen-specific challenge were dependent on both CD4 T cells and CD40-CD40L interactions. Notably, concomitant immunity generated by tumor implantation that can prevent tumor growth on the opposite flank could also occur independently of CD4 T cells, but was lost on CD40L blockade. Systemic vaccination with Listeria monocytogenes expressing SIY efficiently induced the formation of SIY-specific Tcm cells but did not impact tumor implantation. These data suggest that tumor implantation generates Trm cells independently of CD4 T cells, and that these cells, not Tcm cells, sustain concomitant immunity. These data may impact immune therapies designed to control metastatic seeding in patients